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During winter Duffman's blimp comes down because of the snow, a squirrel resembling Scrat from the film Ice age is hit and throw away by groundskeeper Wille and he himself is attacked, Homer wakes up in a pile of snow and does not remember the events of the previous day, commenting that he must have drunk heavily the night before. Homer goes home and finds his family absent. Santa's Little Helper attacks him. Homer travels to Moe’s, where Moe informs him that he was there the previous night and wanted to forget an unpleasant memory. Moe explains he gave Homer a "Forget-Me-Shot", which wiped out the last 24 hours of his memory; the ingredients of which include Jägermeister, sloe gin, triple and quadruple sec, gunk from a dog's eye, Absolut Pickle, the red stripe from Aquafresh toothpaste and the venom of the Louisiana loboto-moth then stirred with a home pregnancy test. Moe also gives a dose of his drink to Krusty who has just triggered a riot at an awards show when a routine went from a "Don Rickles about Arabs" to a "Mel Gibson about Mexicans!" (the Hispanic people of Springfield later decided to use Krusty's prejudice against himself by beating him while he is packed into a piñata, despite Krusty protesting that this only reinforces stereotypes, one of the Hispanic guys clarifies that he is not Mexican, he is from Costa Rica). Chief Wiggum tells Homer that there was a domestic disturbance at his house last night, which was reported by Ned Flanders. Homer instantly receives a flashback to the night before showing Wiggum questioning Marge about a black eye she had received, to which Marge nervously replies that she walked into a door.

A still confused Homer goes home, where a picture of Marge causes a flashback of her pleading Homer to stop, and then rubbing her eye in pain. Horrified, Homer goes to Grampa Simpson for help. Grampa tells Homer about Professor Frink's new machine that helps people sort through their memories. With the help of this technology, Homer sees himself walking in on Marge and Duffman in an allegedly compromising position. In the flashback, Marge tells Homer that she did not want him to find out about it, and Homer assumes that Marge was cheating on him and that Homer beat his wife as payback.

Homer now considers his life to be worthless and decides to commit suicide by jumping off a bridge. He begins to reconsider, but is pushed off by his "guardian angels," Patty and Selma. While falling, Homer's life flashes before his eyes in the form of the YouTube video, "Noah Takes a Photo of Himself Every Day for 6 Years." He then sees the full memory of the preceding night: Marge was planning a surprise party for Homer finishing his community service, and did not want Homer to find out about it. Duffman, who was hired by Marge to entertain at the party, brings out a bottle of DuffChampagne. Overjoyed, Homer tries to open the bottle, while Marge pleads with Homer to stop, as she wants to save it for the party. The cork flies off and hits Marge in the eye. The flashback ends and, instead of falling to his death, Homer lands on a moonbounce, which is at the surprise party on board a ship.

When Homer asks Marge why she lied to Chief Wiggum, she claims that she did not want him at the party, because he would bring Sarah Wiggum, whom Marge does not like. Lenny and Carl appear and cause a flashback which shows Homer telling his bar buddies that he felt very guilty for finding out about the party that Marge worked so hard on. When Moe offers the Forget-Me-Shot (which Moe spat in), Homer predicts exactly what is going to happen, and tells Lenny to make sure there is a moon bounce at the party. Finally, it is revealed that the dog attacked Homer because he does not take care of him.

The scene where Moe tells Homer that he spits in his drinks, just before Homer drinks the "Forget-Me-Shot", copies a similar scene in the film Memento. The episode also vaguely references the film The Game at various points in the episode, especially during the scene when Homer attempts to take his own life.[6] The music playing at the end of the episode is a version of "Day After Day" by Badfinger. When Chief Wiggum asks Homer if he knows who Jack the Ripper was, he answers Queen Victoria's personal doctor. In the chalkboard gag, Bart makes a reference to the hit Disney show Hannah Montana when he's writing "The Capital of Montana is not Hannah"

In its original American broadcast, "Eternal Moonshine of the Simpson Mind" was viewed by an estimated 10.15 million households, won in its time slot, and received a 4.8 rating/12% audience share.[3] Robert Canning of IGN enjoyed the episode, saying it "did both very well by putting Homer in his own head as he tried to recall the events that transpired the previous day. Smart, funny and visually engaging, this episode was an absolute pleasure to watch." He gave it an 8.8/10 rating,[5] and cited it as the season's high point.[8]TV Squad's Richard Keller wrote that "by far, this was the most interesting episode of [the nineteenth season], incorporating humor, romance, and a little bit of science fiction into a tidy little plot. [...] True, it was another Homer-centric episode — one of too many this season, but the writers gave the show enough of a twist to keep it intriguing for the viewer."[6] In another IGN article, Robert Canning, Eric Goldman, Dan Iverson, and Brian Zoromski named "Eternal Moonshine of the Simpson Mind" the best episode of the season, with the rationale that "it's the episode's fantastic visuals that truly make this a memorable episode."[9]

At the 2008Primetime Emmy Awards, the episode won the award for Outstanding Animated Program (for Programming Less Than One Hour).[10] In an interview with Entertainment Weekly regarding the renewal of the show in season 23, showrunner Al Jean discusses what episodes that have previously aired might serve well as a series finale. He regards "Behind the Laughter" and "Eternal Moonshine of the Simpson Mind" as the strongest candidates, and further elaborates: "I don’t think we’re a serialized show and I don’t think we’re going to have a Lost finale where we reveal some truth about the world that nobody ever suspected. Whenever we do a last episode, we just hope that it would be sweet, true to the characters, funny, and give you a nice feeling for where the Simpsons would be headed."[11] In 2012, New York magazine deemed "Eternal Moonshine of the Simpson Mind" one of nine later Simpsons episodes that was as good as the show's classic era.[12]